Risarg (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Overseas Investments AG (Switzerland)

Manufactured By

Novartis Singapore Pharmaceutical Manufacturing Pte. Ltd. (Singapore)

Or

Novartis Pharmaceutical Manufacturing LLC (Slovenia)

Secondary Packaging

SKOPINSKY PHARMACEUTICAL PLANT, CJSC (Russia)

Packaging and Quality Control Release

NOVARTIS PHARMA PRODUCTIONS, GmbH (Germany)

Or

NOVARTIS PHARMA STEIN, AG (Switzerland)

Quality Control Release

SKOPINSKY PHARMACEUTICAL PLANT, CJSC (Russia)

ATC Code

L01EF02 (Ribociclib)

Active Substance

Ribociclib (Rec.INN registered by WHO)

Dosage Form

Risarg

Film-coated tablets, 200 mg: 42 or 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light grayish-violet in color, round, biconvex, with beveled edges; engraved with “RIC” on one side and “NVR” on the other.

Excipients: microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone (type A), magnesium stearate, colloidal silicon dioxide.

Film coating composition white coating premix, black coating premix, red coating premix.
White coating premix polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E171), talc, soy lecithin, xanthan gum.
Black coating premix polyvinyl alcohol (partially hydrolyzed), black iron oxide dye (E172), talc, soy lecithin, xanthan gum.
Red coating premix polyvinyl alcohol (partially hydrolyzed), red iron oxide dye (E172), talc, soy lecithin, xanthan gum.

14 pcs. – blisters (3) – cardboard packs.
21 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent; protein kinase inhibitors; cyclin-dependent kinase (CDK) inhibitors

Pharmacological Action

Antitumor agent, selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. These kinases are activated upon complex formation with D-cyclins and play a key role in signaling pathways regulating the cell cycle and cell proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression by phosphorylating the retinoblastoma protein (pRb).

In vitro, Ribociclib inhibited Rb protein phosphorylation, leading to cell cycle arrest in the G1 phase and reduced cell proliferation in breast cancer cell lines. In vivo, ribociclib monotherapy at well-tolerated doses caused tumor regression, correlating with inhibition of Rb protein phosphorylation. In in vivo studies using patient-derived xenograft models of estrogen receptor-positive breast cancer, the combination of ribociclib and aromatase inhibitors (e.g., letrozole) resulted in greater inhibition of tumor growth compared to each drug alone. After discontinuation of the drug, tumor regrowth was observed after 33 days. Furthermore, the antitumor activity of the ribociclib combination with fulvestrant was evaluated in in vivo studies in immunodeficient mice bearing ZR751 estrogen-enriched breast cancer xenografts. The combination of ribociclib and fulvestrant resulted in complete inhibition of tumor growth.

Pharmacokinetics

After oral administration of ribociclib in patients with advanced solid tumors and lymphomas, the C_max of ribociclib in plasma was reached within 1-4 hours (time to maximum concentration, T_max). A slight supraproportional increase in ribociclib exposure (C_max and area under the concentration-time curve (AUC)) was observed over the studied dose range (from 50 mg to 1200 mg). After repeated once-daily administration, steady state was typically reached after 8 days, with Ribociclib accumulating with a geometric mean ratio of 2.51 (range: 0.972 to 6.40).

The binding of ribociclib to human plasma proteins in vitro was approximately 70% and was concentration-independent (from 10 ng/ml to 10,000 ng/ml). Ribociclib was evenly distributed between erythrocytes and plasma with a mean in vivo blood/plasma ratio of 1.04. According to population pharmacokinetic analysis, the apparent volume of distribution at steady state (Vss/F) was 1090 L.

In vitro and in vivo studies have shown that in humans, Ribociclib undergoes extensive metabolism in the liver primarily via the CYP3A4 isoenzyme. After oral administration of a single 600 mg dose of [¹⁴C] ribociclib to humans, the primary metabolic pathways for ribociclib included oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and their combinations. The primary metabolites of ribociclib underwent conjugation via N-acetylation, sulfation, cysteine conjugation, glycosylation, and glucuronidation. Ribociclib was the main pharmacologically active compound present in plasma (43.5%). The major circulating metabolites: metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation) and M1 (secondary glucuronidation), each accounted for 9.39%, 8.60% and 7.78% of total radioactivity and 21.6%, 19.8% and 17.9% of ribociclib exposure, respectively. The clinical activity (pharmacological properties and safety) of ribociclib was primarily due to the parent substance, with circulating metabolites not being of significant importance.

Ribociclib underwent extensive metabolism, with the amount of unchanged substance being 17.3% and 12.1% in feces and urine, respectively. Metabolite LEQ803 was detected in significant amounts in feces, accounting for 13.9% and 3.74% of the administered dose in feces and urine, respectively. Other metabolites were detected in both feces and urine in small amounts (<2.78% of the administered dose).

At steady state with a 600 mg dose in patients with advanced cancer, the geometric mean effective plasma T_1/2 (based on accumulation ratio) was 32 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/h (66% CV). The geometric mean apparent terminal plasma T_1/2 of ribociclib ranged from 29.7 to 54.7 hours and the geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/h at the 600 mg dose in all studies in healthy volunteers.

Ribociclib is eliminated primarily via the intestine and to a lesser extent by the kidneys. In 6 healthy male volunteers after a single dose of [¹⁴C] ribociclib, 91.7% of the total administered radioactive dose was recovered within 22 days; elimination occurred mainly via the intestine (69.1%), with 22.6% of the dose excreted by the kidneys.

A supraproportional increase in ribociclib exposure (C_max and AUC) was observed after both single and repeated doses in the range from 50 mg to 1200 mg. The data analysis is limited by the small sample size in most cohorts receiving specific doses, with the most data coming from the cohort receiving the 600 mg dose.

Indications

For the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant in women as initial hormonal therapy or in women who have received prior hormonal therapy.

ICD codes

Dosage Regimen

The recommended oral dose is 600 mg (three 200 mg tablets) once daily for 21 consecutive days, followed by a 7-day break to complete a 28-day cycle.

Take tablets at approximately the same time each day, with or without food. Swallow tablets whole; do not chew, crush, or split them.

When used in combination, administer fulvestrant at 500 mg intramuscularly on days 1, 15, 29, and then once monthly. Alternatively, administer an aromatase inhibitor (e.g., letrozole 2.5 mg) once daily continuously throughout the entire 28-day cycle.

Perform complete blood count, liver function tests, and an electrocardiogram prior to initiation. Monitor electrolytes (potassium, calcium, phosphate, magnesium) before starting treatment.

For hematologic toxicity, monitor CBC every 2 weeks for the first 2 cycles, at the beginning of the next 4 cycles, and as clinically indicated thereafter.

For hepatotoxicity, monitor liver function every 2 weeks for the first 2 cycles, at the beginning of the next 4 cycles, and as clinically indicated.

Repeat ECG approximately on day 14 of the first cycle and at the beginning of the second cycle.

In case of adverse reactions, implement dose interruption, dose reduction, or discontinuation as clinically warranted. The first dose reduction is to 400 mg daily; the second dose reduction is to 200 mg daily.

Discontinue permanently if dosage at 200 mg daily is not tolerated. Do not initiate therapy in patients with a QTcF interval >450 msec.

Avoid concomitant use with potent CYP3A inhibitors or inducers. If use with a potent CYP3A inhibitor is unavoidable, reduce the Ribociclib dose to 200 mg. Avoid grapefruit and grapefruit juice.

Adverse Reactions

Infections and parasitic diseases very common – urinary tract infections, respiratory tract infections, gastroenteritis, sepsis (< 1).

Blood and lymphatic system disorders very common – neutropenia, leukopenia, anemia; common – lymphopenia, thrombocytopenia, febrile neutropenia.

Eye disorders common – lacrimation, dry eye.

Metabolism and nutrition disorders very common – decreased appetite; common – hypocalcemia, hypokalemia, hypophosphatemia.

Nervous system disorders very common – headache, dizziness; common – vertigo.

Cardiac disorders syncope.

Respiratory, thoracic and mediastinal disorders very common – dyspnea, cough.

Musculoskeletal and connective tissue disorders: very common – back pain.

Gastrointestinal disorders: very common – nausea, diarrhea, vomiting, constipation, stomatitis, abdominal pain, upper abdominal pain; common – dysgeusia, dyspepsia.

Hepatobiliary disorders: common – hepatotoxicity (hepatocellular damage, drug-induced liver injury, hepatotoxicity, hepatic failure, autoimmune hepatitis (single case)).

Skin and subcutaneous tissue disorders very common – alopecia, skin rash (rash, maculopapular rash, pruritic rash), pruritus; common – erythema, dry skin, vitiligo.

General disorders and administration site conditions: very common – fatigue, peripheral edema, asthenia, pyrexia; common – dry mouth, oropharyngeal pain.

Investigations: very common – increased ALT, increased AST, increased serum bilirubin; common – increased serum creatinine, electrocardiogram QT prolonged.

Contraindications

Age under 18 years, pregnancy and breastfeeding period.

With caution

In patients with grade 3-4 neutropenia, with severe renal impairment, in patients with hepatobiliary toxicity, in patients with existing or significant risk of QT interval prolongation (long QT syndrome, uncontrolled or clinically significant cardiac disease, including recent myocardial infarction, chronic heart failure, unstable angina and bradyarrhythmia, electrolyte imbalances), with concomitant use of drugs that prolong the QTc interval, with potent inhibitors of the CYP3A isoenzyme, when used with substrates of the CYP3A isoenzyme with a narrow therapeutic index.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and breastfeeding.

Pediatric Use

Use is contraindicated in children under 18 years of age.

Special Precautions

In patients receiving Ribociclib in combination with an aromatase inhibitor/fulvestrant (+/- GnRH) in Phase III clinical trials, the most frequent adverse reaction was neutropenia (73.7%) and grade 3 or 4 neutrophil count decrease (based on laboratory data) was observed in 58.4% of patients. Among patients who experienced grade 2, 3, or 4 neutropenia in Phase III clinical trials, the median time to onset of grade 2, 3, or 4 neutropenia was 16 days. The median time to resolution of grade >3 neutropenia (to normalization or decrease to <grade 3) was 12 days in the treatment group with any investigational combination. The severity of neutropenia was concentration-dependent. In patients receiving Ribociclib in Phase III clinical trials, febrile neutropenia developed in 1.4% of patients. The patient must be informed by the physician of the need to urgently report any cases of fever.

A complete blood count (CBC) should be performed before starting therapy. CBC monitoring is required every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and then as clinically indicated.

In case of severe neutropenia, temporary discontinuation of the drug, dose reduction, or complete withdrawal may be required. In patients developing grade 1 or 2 neutropenia, no dose adjustment is required. In patients developing grade 3 neutropenia without fever, administration should be temporarily withheld until recovery to <grade 2, and then resumed at the same dose. Upon recurrence of grade 3 neutropenia without fever, the drug should be temporarily withheld until recovery, then resumed at a dose reduced to the next level. In patients with grade 3 febrile neutropenia (ANC from 500 to <1000/mm³ with a single episode of fever >38.3°C (100.9°F) (or) above 38°C (100.4°F) for more than 1 hour and/or with concurrent infection), or in patients developing grade 4 neutropenia, administration should be temporarily withheld until neutropenia recovers to <grade 2, then should be resumed at a dose reduced to the next level.

Increased transaminase activity was observed in Phase III clinical trials. Increased ALT (9.7% vs. 1.5%) and AST (6.7% vs. 2.1%) of grade 3 or 4 were reported in the groups of patients receiving Ribociclib in combination with any investigational combination and in the placebo group in combination with any investigational combination, respectively.

Liver function tests should be performed before starting therapy with the drug. Liver function should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and then as clinically indicated. In case of marked increase in transaminase activity, temporary discontinuation, dose reduction, or complete withdrawal may be required.

In Phase III studies, review of ECG data from patients with advanced or metastatic breast cancer who received therapy with this drug in combination with any investigational combination showed that in 14 patients (1.3%) the post-baseline QTcF value was >500 msec, and 59 patients (5.6%) had a QTcF interval increase >60 msec from baseline. No cases of torsades de pointes were reported.

Tamoxifen contributes to the risk of QTcF interval prolongation, which may contribute to the QTcF interval value when taking the combination of ribociclib with tamoxifen. An increase in QTcF >60 msec from baseline was observed in 6/90 (6.7%) patients in the placebo group in combination with tamoxifen, in 14/87 (16.1%) patients in the ribociclib group in combination with tamoxifen, and in 18/245 (7.3%) patients in the ribociclib group in combination with nonsteroidal aromatase inhibitors.

An ECG should be performed before starting treatment. Ribociclib treatment should only be initiated in patients with a QTcF duration of less than 450 msec. Repeat ECG is required approximately on day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated.

Appropriate monitoring of serum electrolyte levels (including potassium, calcium, phosphate, and magnesium) should be performed before starting treatment, at the beginning of the first 6 cycles, and then as clinically indicated. Any electrolyte abnormalities should be corrected before starting and during ribociclib therapy.

Use of the drug should be avoided in patients with existing or significant risk of QTc interval prolongation, including: long QT syndrome; uncontrolled or clinically significant cardiac disease, including recent myocardial infarction, chronic heart failure, unstable angina and bradyarrhythmia; electrolyte imbalances.

Concomitant use of ribociclib with drugs that can prolong the QTc interval and/or are potent inhibitors of the CYP3A isoenzyme should be avoided, as this may lead to clinically significant prolongation of the QTcF interval. If QT interval prolongation is detected, temporary discontinuation, dose reduction, or complete withdrawal of the drug may be required. Based on Phase III clinical trial data, Ribociclib is not recommended to be taken in combination with tamoxifen due to a significant increase in tamoxifen-mediated risk of QTcF interval prolongation.

Effect on ability to drive vehicles and operate machinery

Patients should exercise caution when driving vehicles and/or operating machinery, considering the possibility of increased fatigue during drug use.

Drug Interactions

Ribociclib metabolism occurs primarily via the CYP3A isoenzyme. In vivo, Ribociclib is a time-dependent inhibitor of the CYP3A isoenzyme. Therefore, drugs that affect the enzymatic activity of the CYP3A isoenzyme can alter the pharmacokinetics of ribociclib.

Concomitant use with potent inhibitors of the CYP3A isoenzyme should be avoided, including (but not limited to) the following drugs: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole. If concomitant use of the drug with a potent inhibitor of the CYP3A isoenzyme cannot be avoided, the ribociclib dose should be reduced to 200 mg.

The patient should be informed to avoid consuming grapefruit or grapefruit juice and all products known as inhibitors of the CYP3A isoenzyme that may increase ribociclib exposure.

Concomitant use with potent inducers of the CYP3A isoenzyme should be avoided, including (but not limited to) the following drugs: phenytoin, rifampicin, carbamazepine, and St. John’s wort (Hypericum perforatum).

When used concomitantly in healthy volunteers with the CYP3A4 isoenzyme substrate midazolam and multiple doses of the medicinal product (400 mg), the exposure of midazolam increases by 280% (3.80-fold) compared to taking midazolam alone.

Caution is recommended when using the medicinal product and CYP3A isoenzyme substrates with a narrow therapeutic index.

A dose reduction of the sensitive CYP3A isoenzyme substrate with a narrow therapeutic index may be required, including (but not limited to) the following drugs: alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, as Ribociclib has the ability to increase their exposure.

In vitro studies have shown that Ribociclib at clinically significant concentrations has a low potential for inhibiting the activity of the drug transporters P-glycoprotein, OAT1/3, OATP1B1/B3, and OCT1.

At clinical concentrations, Ribociclib is capable of inhibiting Breast Cancer Resistance Protein (BCRP), OCT2, MATE1, and the human Bile Salt Export Pump (BSEP).

Concomitant use with drugs known to prolong the QT interval, such as antiarrhythmic agents, should be avoided.

Concomitant use of the following antiarrhythmic drugs should be avoided (including, but not limited to): amiodarone, disopyramide, procainamide, quinidine, and sotalol; other drugs that prolong the QT interval (including, but not limited to): chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide, and intravenously administered ondansetron.

It is not recommended to use in combination with tamoxifen.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.